New acyclonucleosides: Synthesis and anti-HIV activity

Article abstract of DOI:10.1081/NCN-200067423

The synthesis of new acyclic nucleosides is described. These syntheses were accomplished by various methods: glycosylation, selective or total deprotection, oxidation/reduction, chlorination or azidation of hydroxyl groups. The compounds were characterized with NMR, mass and IR spectroscopy. Antiviral properties of these compounds were evaluated on HIV-1 infected cell lines. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200067423

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New Acyclonucleosides: Synthesis and Anti-HIV Activity
Amel Hadj-Bouazza a , Rachida Zerrouki a , Pierre Krausz a , Géraldine Laumond b , Anne
Marie Aubertin b & Yves Champavier c
a Laboratoire de Chimie des Substances Naturelles, Faculté des Sciences et Techniques ,
Université de Limoges , Limoges, France
b INSERM U 544, Institut de virologie , Université Louis Pasteur , Strasbourg, France
c Service Commun de RMN, Faculté de Pharmacie , Université de Limoges , Limoges, France
Published online: 31 Aug 2006.
To cite this article: Amel Hadj-Bouazza , Rachida Zerrouki , Pierre Krausz , Géraldine Laumond , Anne Marie Aubertin & Yves
Champavier (2005) New Acyclonucleosides: Synthesis and Anti-HIV Activity, Nucleosides, Nucleotides and Nucleic Acids, 24:8,
1249-1263, DOI: 10.1081/NCN-200067423
To link to this article: http://dx.doi.org/10.1081/NCN-200067423
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (8):1249–1263, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200067423
NEW ACYCLONUCLEOSIDES: SYNTHESIS AND ANTI-HIV ACTIVITY
5
Amel Hadj-Bouazza, Rachida Zerrouki, and Pierre Krausz
Laboratoire de Chimie
des Substances Naturelles, Faculte´ des Sciences et Techniques, Universite´ de Limoges, Limoges,
France
5
G´eraldine Laumond and Anne Marie Aubertin
INSERM U 544, Institut de
virologie, Universite´ Louis Pasteur, Strasbourg, France
5
Yves Champavier
Service Commun de RMN, Faculte´ de Pharmacie, Universite´ de
Limoges, Limoges, France
5
The synthesis of new acyclic nucleosides is described. These syntheses were accomplished by various
methods: glycosylation, selective or total deprotection, oxidation/reduction, chlorination or azidation of
hydroxyl groups. The compounds were characterized with NMR, mass and IR spectroscopy. Antiviral
properties of these compounds were evaluated on HIV-1 infected cell lines.
Keywords Acyclonucleoside, Selective Deprotection, Azidation, Chlorination
INTRODUCTION
For several years, there has been an intensive search for drugs effective in the
chemotherapy of viral infections by, e.g., HIV, herpes simplex or cytomegalovi-
rus.[1–4] Most of these drugs are analogues of naturally accuring nucleosides.[5]
The introduction of acyclovir[6] as a clinically useful antiviral drug has spurred
interest in acyclic nucleosides as potential chemotherapeutic agents. Consequently,
many different families of nucleoside analogues and acyclonucleosides[7,8] have
been synthesized and tested in order to enhance biological activity and selectivity,
or to lower their toxicity.
Continuing with our work in this field,[9,10] we report here the synthesis of azido
or chloro acyclonucleosides with N-3 modified thymine, to determine the influence
of the azido, chloro or carboxymethyl groups on anti-HIV activity.
Received 7 September 2004, accepted 4 April 2005.
Address correspondence to Rachida Zerrouki, Laboratoire de Chimie des Substances Naturelles, Facult´e des
Sciences et Techniques, Universit´e de Limoges, 123, Av. Albert Thomas, Limoges 87060, France; E-mail:
rachida.zerrouki@unilim.fr
1249
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1250
A. Hadj-Bouazza et al.
RESULTS AND DISCUSSION
Chemistry
The starting material 1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)thymine (1) was
prepared using the classical method of Vorbru¨ggen.[11,12] Thymine was silylated in
dry 1,2-dichloroethane with TMSC1 (0.8 equiv.) and HMDS (0.8 equiv.). The
reaction was continued by addition of a solution of 1-O-acetyl-2,3,5-tribenzoylribo-
furanose (1 equiv.) and a Lewis acid in 1,2-dichloroethane. Two equivalents of
SnCl4 are needed for the reaction because of the inhibition due to excess of
silylation reagents in solution. Compound 1 was obtained in 91% yield. Alkylation
of thymine with tert-butyl bromoacetate in the presence of potassium carbonate in
N,N-dimethylformamide gave compound 2 in quantitative yield (Scheme 1). The
tert-butyl ester was selected because it is stable in presence of ammonia, which was
later used for deprotection of hydroxyl groups.
The next step was the selective or total deprotection of sugar moiety
(Scheme 2). The removal of benzoyl groups from 1 to give the unprotected
compound 3 proceeded readily with sodium methoxide in 98% yield. Using the
same method for total deprotection of 2 gave a mixture of two products. Structural
elucidation of these compounds indicated that one of them is the expected product
4 (50%) and the second one 4’ (24%) results from total deprotection and trans-
esterification. Compound 2 was then debenzoylated using an excess of ammonia in
methanol (88.9%).
For selective deprotection of compounds 1 and 2, we have found that
secondary hydroxyl groups can be efficiently and selectively generated from their
benzoylated forms by controlling the amount of NH3, reaction time, and
temperature. The best results were obtained at À15°C using 25 equivalents of
ammonia per benzoyl protected secondary hydroxyl group. The reaction was
checked by TLC and stopped by evaporation, as soon as the trihydroxyl derivatives
showed up. This method requires no particular precaution and implies an easy
work up (concentration of the reaction mixture). Compounds 5 and 6 were
obtained after purification in 68% and 66.6% yields, respectively.
The 2’,3’-seconucleosides 7--10 retain the carbon framework of ribose
nucleosides and chirality of the anomeric carbon, yet allow for greater flexibility
than the furanose moiety. The synthetic route chosen for these analogues was
periodate oxidation and reduction of obtained dialdehyde with borohydride
SCHEME 1 Glycosylation/N-alkylation.

New Acyclonucleosides
1251
SCHEME 2 Selective or total deprotection of hydroxyl groups.
(Scheme 3). This transformation was carried out in one step, using periodate and
borohydride bound resins.[13–18] The final products 7--10 were easily recovered
after filtration of the reaction mixture followed by evaporation of the filtrate and
purification.
The introduction of an azide function was achieved in two steps. The first one is
mesylation of acyclonucleosides in the presence of mesyl chloride in anhydrous
pyridine at 0°C. The crude mixture was used in second step without purification.
Azidation was carried out in DMF at 100°C in the presence of NaN3. After
purification, compounds 11--14 were obtained in 47.7–61.6% overall yield,
comparable to literature values (Scheme 4).
Chlorination of compound 7 with an excess of thionyl chloride in di-
methylformamide, for 3 days at room temperature gave compound 15 in lower
yield (30%). The use of pyridine as a solvent leads to product 15 in acceptable yield
(60.4%). This reaction was applied to compounds 8--10 to give corresponding
chlorinated compounds 16--18 (Scheme 5).
The deprotection of 5’-benzoyl group was realized by methanolic ammonia
solution (7 M), after 4 days, compounds 13 and 14 gives 19 and 20 in 70% and
80% yield, respectively (Scheme 6).
SCHEME 3 Reaction of oxidation/reduction.

1252
A. Hadj-Bouazza et al.
SCHEME 4 Preparation of azido compounds.
Deprotection of compound 17 with methanolic ammonia gives a product
resulting from debenzoylation of primary hydroxyl group and intramolecular
cyclization. Mass spectroscopy of compound 21 presents two peaks representing
MH+ (261) and MNH+4 (278). H NMR confirms the structure and shows the
1
presence of two compounds. The diastereoselectivity of the cyclization was 63/37,
but we have not determined the relative configurations (Scheme 7). The same
cyclization was observed (by mass spectroscopy) when the reaction of deprotection
of compound 18 was realized.
Finally, compounds 8, 12, 16, and 20 were treated with TFA giving the
desired derivatives 23 in quantitative yield, 24, 25, and 26 in 87.6%, 83% and 52%
yield respectively (Scheme 8).
Biological Evaluation
The synthesized compounds 7, 11, 15, 19, 22, 23, 24, and 25 were tested
for their in vitro inhibitory effects on the replication of RNA virus (HIV-1). The anti
HIV 1 activity was tested on CEM-SS and MT4 infected respectively with HIV-1
LAI and HIV IIIB according to protocols described previously.[19] In the case
of CEM-SS cells, the production of virus was measured by quantification of re-
verse transcriptase activity associated with the releasing of virus particles in the
culture supernatant; for MT4 cells, the assay was based on the virus induced
SCHEME 5 Chlorination of acyclonucleosides.

New Acyclonucleosides
1253
SCHEME 6 Deprotection of primary hydroxyl group.
cytopathogenicity. Cell viability was evaluated by measuring the activity of
mitochondrial electron transport by the MTT assay.[20] The antiviral activity is
expressed as EC50, the concentration of the compound necessary to reduce virus
replication by 50% and was derived from the computer-generated median effect plot
of the dose-effect data.[21] The cytotoxicity is expressed as CC50, the concentration
of drug needed to reduce the viability of uninfected cells by 50%. The results are
summarized in Table 1. For infected CEM-SS cells, the selectivity index (SI = ratio
CC50/EC50) is low and close to 2, indicating that the compound have no specific
antiviral activity. Similar results can be derived from the MT4 assay as no protection
against the virus induced cytopathic effect was observed in presence of the drug.
EXPERIMENTAL SECTION
All the solvents and chemicals were commercially available and, unless
otherwise stated, were used as received. DMF and ClCH2CH2Cl were distilled
twice over P2O5 and over CaH2 just before use. Reactions were monitored by thin-
layer chromatography (TLC) on precoated 0.2 mm silica gel 60 F254 (Merck) plates
and visualized in several ways: with an ultraviolet light source at 254 nm, by
spraying with sulfuric acid (6N) and heating to 200°C. Silica gel (Merck Kieselgel
60, 15–40 mm) was used for flash chromatography. 1H NMR spectra were recorded
at 400.13 MHz with a Bru¨ker DPX spectrometer. Chemical shifts (d) are expressed
in ppm with Me4Si as internal standard (d = 0). Data are reported as follows:
chemical shift, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; q, quintet; m,
SCHEME 7 Intramolecular cyclization.

1254
A. Hadj-Bouazza et al.
SCHEME 8 Deprotection of carboxyl group.
multiplet and br, broad), coupling constants (Hz) and assignment. Melting points
(mp) were determined with a Kofler block and are uncorrected. Rotatory dis-
persions were measured with a Jasco (DIP-370) polarimeter in a 1 dm quartz cell at
22°C. IR spectra were recorded on a Perkin Elmer 1310 grating spectrophotometer
and are reported in wave number (cmÀ1). Chemical-impact mass spectra (CI) was
recorded with a Kratos MS 580 mass spectrometer at the laboratoire de Chimie
Organique Structurale of the Universit´e Pierre et Marie Curie (Paris VI).
1-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)thymine (1). To thy-
mine (4 mmol, 0.504 g) in dry dichloroethane (20 mL) was added (0.676 mL, 0.8 eq)
HMDS and (0.3 mL, 0.8 eq) TMSC1. The reaction mixture was heated at 80°C for
3 h. After cooling to room temperature a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-b-
D-ribofuranose (2.016 g, 1 eq) in dichloroethane (20 mL) was added followed
by SnCl4 (0.932 mL, 2 eq). The solution was stirred at room temperature until
TLC indicated the completion of the reaction (2 h). The reaction mixture was
quenched by NaHCO3 saturated water solution and extracted with chloroform.
TABLE 1 Antiviral Effects of Derivatives of Acyclonucleosides
CEM-SS
MT-4
a
b
a
b
Compound
EC50
CC50
EC50
CC50
7
>1.10À1
>1.10À1
>CC5À01
>1.10À1
>1.10
>1.10À1
>1.10À1
>1.10À1
>1.10À1
>1.10À1
7.610À2
>1.10À1
>1.10À1
>1.10À1
>1.10À1
>1.10À1
>1.10À1
>1.10À1
>CC50
>CC5À01
>1.10À1
>1.10
>1.10À1
>1.10À1
>1.10À1
>1.10À1
1.10À1
11
15
19
22
23
24
25
7.81À0À1 2
>1.10À1
>1.10À1
>1.10
>1.10À1
a50% Effective concentration (mg/mL) or concentration required to inhibition the replication of HIV-1 by 50%.
b50% Cytotoxic concentration (mg/mL) or concentration required to reduce the viability of uninfected cells
by 50%.

New Acyclonucleosides
1255
The chloroform solution was dried over MgSO4 and the solvent was removed by
evaporation under reduced pressure. The crude product was purified by
chromatography on silica gel (elution with a gradient of dichloromethane/ethanol).
Compound 1 was isolated as a white solid (2.07 g, 91%). Rf = 0.53 (CH2Cl2/EtOH,
97/3, v/v); mp = 94°C; [a]D = À21.1° (c = 1, CHCl3); IR: 3186 (N–H), 3065 (C–H),
1
1724 (C = O benzoyl), 1694 (C = O thym), 1603 (C = C), 1266 (C–O–C); H
NMR (CDCl3) d 8.8 (s, 1H, N–H), 8.2–7.35 (m, 15H, Ar), 7.16 (q, 1H, JH6,CH3 =1.0
Hz, H-6), 6.43 (d, 1H, J1’,2’ = 6.2 Hz, H-1’), 5.91 (dd, 1H, J3’,2’ = 6.2 Hz, J3’,4’ = 3.7
Hz, H-3’), 5.76 (t, 1H, H-2’), 4.88 (dd, 1H, J5’a,5’b = 12.1 Hz, J5’a,4’ = 2.5 Hz, H-5’a),
4.70 (m, 1H, H-4’), 4.65 (dd, 1H, J5’b,4’ = 3.4 Hz, H-5’b), 1.60 (d, 3H, JCH3,H6 = 1.0
Hz, CH3).
1-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-3-tert-butoxycarbon-
ylmethylthymine (2). To a solution of 1-(2,3,5-Tri-O-benzoyl-b-D-ribofur-
anosyl)thymine (300 mg, 0.526 mmol) in DMF (10 mL) was added K2CO3 (725 mg,
10 eq), after ten minutes tert-butyl bromoacetate (0.155 mL, 2 eq) was added and
the reaction mixture was stirred at room temperature for two hours. The solution
was filtered and the K2CO3 washed with dichloroethane. The crude product was
subjected to preparative TLC using CH2Cl2/EtOH (99.5/0.5, v/v) yielding 2 (356
mg, 99%) as a sirup. Rf = 0.56 (CH2Cl2/EtOH, 97/3, v/v); [a]D = À63.6° (c = 0.91,
CHCl3); IR: 2973 (C–H), 1728 (C = O benzoyl), 1694 (C = O thym), 1667 (C = O
1
CO2tBu), 1599 (C = C), 1266 (C–O–C); H NMR (CDCl3) d 8.2–7.34 (m,
15H, Ar), 7.20 (brs, 1H, H-6), 6.45 (d, 1H, J1’,2’ = 6.0 Hz, H-1’), 5.93 (dd, 1H,
J3’,2’ = 6.0 Hz, J3’,4’ = 4.2 Hz, H-3’), 5.75 (t, 1H, H-2’), 4.88 (dd, 1H, J5’a,5’b = 12.2 Hz,
J5’a,4’ = 2.4 Hz, H-5’a), 4.70 (m, 1H, H-4’), 4.64 (dd, 1H, J5’b,4’ = 3.3 Hz, H-5’b),
4.58 (d, 1H, J = 16.5, CH2), 4.52 (d, 1H, J = 16.5, CH2), 1.64 (brs, 3H, CH3), 1.42
(s, 9H, tBu).
1-(b-D-Ribofuranosyl)thymine (3). 1-(2,3,5-Tri-O-benzoyl-b-D-ribo-
furanosyl)thymine (1) (500 mg, 0.877 mmol) was dissolved in a 7 M solution of
ammonia in methanol (19 mL, 150 eq). After 4 days the solution was evaporated to
dryness. The crude product was subjected to preparative TLC (CH2Cl2/EtOH, 70/
30, v/v) yielding 98% (222 mg). Rf = 0.54 (CH2Cl2/EtOH, 90/10, v/v); [a]D = À12.9°
1
(c = 0.43, CH3OH); IR: 3365 (O–H), 2933 (C–H), 1694 (C = O thym); H NMR
(CDCl3) d 7.83 (q, 1H, JH6,CH3 = 1.0 Hz, H-6), 5.89 (d, 1H, J1’,2’ = 4.4 Hz, H-1’), 4.19
(dd, 1H, J2’3’ = 5.3 Hz, H-2’), 4.15 (dd, 1H, J3’,4’ = 4.0 Hz, H-3’), 3.88 (ddd, 1H,
J5’a,4’ = 2.7 Hz, J5’b,4’ = 3.0 Hz, H-4’), 3.84 (dd, 1H, J5’a,5’b = 12.2 Hz, H-5’a), 3.73
(dd, 1H, H-5’b), 1.87 (d, 3H, JCH3,H6 = 1.0 Hz, CH3).
3-tert-Butoxycarbonylmethyl-1-(b-D-ribofuranosyl)thymine
(4). Compound 4 was prepared according to the procedure described for 3
starting from 2 (110 mg, 0.16 mmol). Yield 88.9% (53 mg); Rf = 0.54 (CH2Cl2/
EtOH, 90/10, v/v); IR: 3379 (O–H), 2936 (C–H), 1703 (C = O thym), 1661 (C = O

1256
A. Hadj-Bouazza et al.
1
CO2tBu), 1636 (C = C), 1240 (C–O–C); H NMR (CD3OD) d 7.95 (d, 1H,
JH6,CH3 = 1.0 Hz, H-6), 5.90 (d, 1H, J1’,2’ = 4.4 Hz, H-1’), 4.55 (s, 2H, CH2), 4.35 (t,
1H, J3’,2’ = J3’,4’ = 4.6 Hz, H-3’), 4.26 (t, 1H, H-2’), 4.00 (ddd, 1H, J4’,5’a = 2.6 Hz,
J4’,5’b = 2.9 Hz, H-4’), 3.87 (dd, 1H, J5’a,5’b = 12.2 Hz, H-5’a), 3.75 (dd, 1H, H-5’b),
1.91 (d, 3H, JCH3,H6 = 1.0 Hz, CH3), 1.46 (s, 9H, tBu).
1-(5-O-Benzoyl-b-D-ribofuranosyl)thymine (5). A solution of 1-(2,3,
5-Tri-O-benzoyl-b-D-ribofuranosyl)thymine (499 mg, 0.875 mmol) in methanol (15 mL)
and 6.25 mL of solution of ammonia in methanol (7 M) was stirred at À15°C. After
7 h the solution was evaporated to dryness in a cold bath. The crude product was
purified using preparative TLC (CH2Cl2/EtOH, 97/3, v/v) pure 5 was recovered in
68% yield (215 mg). Rf = 0.21 (CH2Cl2/EtOH, 97/3, v/v); IR: 3360 (O–H), 2953 (C–
H), 1710 (C = O benzoyl), 1670 (C = O thym), 1265 (C–O–C); 1H NMR (CD3OD)
d 8.10–7.40 (m, 5H, Ar), 7.35 (d, 1H, JH6,CH3 = 1.0 Hz, H-6), 5.88 (d, 1H, J1’, 2’ = 4.4
Hz, H-1’), 4.71 (dd, 1H, J5’a,5’b = 12.2 Hz, J5’a,4’ = 2.9 Hz, H-5’a), 4.51 (dd, 1H,
J5’b,4’ = 4.0 Hz, H-5’b), 4.27 (m, 1H, H-4’), 4.27 (m, 1H, H-3’), 4.26 (t, 1H, J2’,3’ = 4,4
Hz, H-2’), 1.59 (d, 3H, JCH3,H6 = 1.0, CH3).
1-(5-O-Benzoyl-b-D-ribofuranosyl)-3-tert-butoxycarbonylme-
thylthymine (6). Compound 6 was prepared the same way as that de-
scribed for 5 starting from 2 (200 mg, 0.29 mmol). Yield 66.6% (92 mg); Rf = 0.50
(CH2Cl2/EtOH, 97/3, v/v); IR: 3365 (O–H), 2947 (C–H), 1711 (C = O benzoyl),
1665 (C = O thym), 1660 (C = O CO2tBu), 1271 (C–O–C); 1H NMR (CD3OD) d
8.05 (dd, 2H, J = 7.4 Hz, J = 1.0 Hz, Ar), 7.63 (brt, 1H, J = 7.4 Hz, Ar), 7.50 (t, 2H,
J = 7.4 Hz, Ar), 7.44 (d, 1H, JH6,CH3 = 1.0 Hz, H-6), 5.83 (d, 1H, J1’,2’ = 4.0 Hz,
H-1’), 4.73 (dd, 1H, J5’a,5’b = 12.4 Hz, J5’a,4’ = 2.4 Hz, H-5’a), 4.54 (s, 2H, CH2),
4.52 (dd, 1H, J5’b,4’ = 4.0 Hz, H-5’b), 4.42 (m, 1H, H-4’), 4.32 (t, 1H, J3’,4’
=
J3’,2’ = 5.0 Hz, H-3’), 4.27 (dd, 1H, H-2’), 1.68 (d, 3H, JCH3,H6 = 1.0 Hz, CH3), 1.45
(s, 9H, tBu).
1-[1-(1,3-Dihydroxyisopropoxy)-2-hydroxyethyl]thymine (7).
To a solution of 3 (430 mg, 1.666 mmol) in methanol (38 mL) were added 1.88 g
each of periodate and borohydride resins. The mixture was stirred at room
temperature until reaction was complete (4 days). The intermediate dialdehyde had
a higher Rf and the final diol had a lower Rf than the starting compound. The resin
beds were filtered and washed with methanol. The methanol filtrate was evaporated
under reduced pressure to obtain the desired acyclic product in 64.6% yield (280
mg). Rf = 0.58 (CH2Cl2/EtOH, 90/10, v/v); IR: 3395 (O–H), 2955 (C–H), 1673
(C = O thym), 1269 (C–O–C); 1H NMR (CD3OD) d 7.6 (d, 1H, JH6,CH3 = 1.1 Hz,
H-6), 5.96 (t, 1H, J1’,2’ = 5.5 Hz, H-1’), 3.79 (dd, 1H, J2’a,2’b = 11.9 Hz, H-2’a), 3.70
(dd, 1H, H-2’b), 3.69 (m, 1H, H-3’a), 3.68 (dd, 1H, J3’a,3’b = 12.5 Hz, J3’4’ = 6.3 Hz,
H-3’b), 3.58 (dd, 1H, J5’a,5’b = 12.0 Hz, J5’a,4’ = 5.4 Hz, H-5’a), 3.57 (m, 1H, H-4’),
3.56 (dd, 1H, J5’b,4’ = 5.3 Hz, H-5’b), 1.91 (d, 3H, JCH3,H6 = 1.1 Hz, CH3).

New Acyclonucleosides
1257
Compounds 8, 9 and 10 were prepared according to the procedure described
for 7 starting from 4 (102 mg, 0.274 mmol), 5 (250 mg, 0.69 mmol), and 6 (92 mg,
0.193 mmol).
1-[1-(1,3-Dihydroxyisopropoxy)-2-hydroxyethyl]-3-tert-butox-
ycarbonylmethylthymine (8). Yield: 91.7% (94 mg); Rf = 0.55 (CH2Cl2/
EtOH, 90/10, v/v); IR: 3420 (O–H), 2927 (C–H), 1700 (C = O thym), 1666 (C = O
CO2tBu), 1251 (C–O–C); 1H NMR (CD3OD) d: 7.65 (q, 1H, JH6,CH3 = 1.0 Hz, H-
6), 5.97 (t, 1H, J1’,2’ = 5.4 Hz, H-1’), 4.56 (s, 2H, CH2), 3.77 (dd, 1H, J2’a,2’b = 11.9
Hz, J2’a,1’ = 5.4 Hz, H-2’a), 3.74 (dd, 1H, J5’a,5’b = 11.6 Hz, J5’a,4’ = 3.9 Hz, H-5’a),
3.71 (m, 1H, H-4’), 3.69 (dd, 1H, J2’b,1’ = 5.4 Hz, H-2’b), 3.63 (dd, 1H, J3’a,3’b = 11.9
Hz, J3’a,4’ = 5.0 Hz, H-3’a), 3.56 (dd, 1H, J3’b,4’ = 2.2 Hz, H-3’b), 3.55 (m, 1H, H-5’b),
1.93 (d, 3H, JCH3,H6 = 1.0 Hz, CH3), 1.46 (s, 9H, tBu).
1-[1-(1-O-Benzoylmethyl-2-hydroxyethoxy)-2-hydroxy-
ethyl]thymine (9). Yield: 79.6% (200 mg), Rf = 0.50 (CH2Cl2/EtOH, 90/10,
v/v); IR: 3397 (O–H), 2935 (C–H), 1720 (C = O benzoyl), 1698 (C = O thym),
1
1270 (C–O–C); H NMR (CD3OD) d: 8.10–7.40 (m, 5H, Ar), 7.36 (d, 1H,
JH6,CH3 = 1.0 Hz, H-6), 5.95 (t, 1H, J1’,2’ = 5.7 Hz, H-1’), 4.00 (m, 1H, H-4’), 3.80 (dd,
1H, J5’a,5’b = 12.0 Hz, J5’a,4’ = 4.8 Hz, H-5’a), 3.78 (dd, 1H, J2’a,2’b = 12.0 Hz, H-2’a),
3.74 (dd, 1H, J5’b,4’ = 5.3 Hz, H-5’b), 3.68 (dd, 1H, J3’a,3’b = 12.2 Hz, J3’a,4’ = 2.2 Hz,
H-3’a), 3.67 (dd, 1H, J3’b,4’ = 4.0 Hz, H-3’b), 3.65 (dd, 1H, H-2’b), 1.46 (d, 3H,
JCH3,H6 = 1.0 Hz, CH3).
1-[1-(1-O-Benzoylmethyl-2-hydroxyethoxy)-2-hydroxyethyl]-3-
tert-butoxycarbonyl methylthymine (10). Yield: 97.4% (90 mg);
Rf = 0.63 (CH2Cl2/EtOH, 95/5, v/v); IR: 3399 (O–H), 2930 (C–H), 1725 (C = O
1
benzoyl), 1699 (C = O thym), 1661 (C = O CO2tBu), 1271 (C–O–C); H NMR
(CD3OD) d: 7.95–7.41 (m, 5H, Ar), 7.4 (d, 1H, JH6,CH3 = 1.0 Hz, H-6), 5.99 (t, 1H,
J1’,2’ = 5.6 Hz, H-1’), 4.50 (s, 2H, CH2), 4.42 (m, 1H, H-5’a), 4.30 (dd, 1H, J5’a,5’b
=
12.0 Hz, J5’b,4’ = 2.7 Hz, H-5’b), 4.02 (m, 1H, H-4’), 3.81 (dd, 1H, J2’a,2’b = 12.0 Hz,
H-2’a), 3.78 (dd, 1H, J3’a,3’b = 11.9 Hz, J3’a,4’ = 4.8 Hz, H-3’a), 3.75 (dd, 1H,
J3’b,4’ = 5.4 Hz, H-3’b), 3.67 (dd, 1H, H-2’b), 1.58 (d, 3H, JCH3,H6 = 1.0 Hz, CH3),
1.46 (s, 9H, tBu).
1-[1-(1,3-Azidoisopropoxy)-2-azidoethyl]thymine (11). To a
solution of compound 7 (329 mg, 1.26 mmol) in a pyridine (4.5 mL) at 0°C were
added 12 equivalents of mesyl chloride (0.860 mL). After two h, the solution was
quenched with the addition of a NaHCO3 saturated water solution and extracted
with CHCl3. The organic layer was dried (MgSO4), filtered, and the solvent
removed. The resulting product (262 mg, 0.53 mmol) was dissolved in DMF (5 mL).
This solution was immersed in an oil bath at 100°C and sodium azide (524 mg, 15 eq)
was added. After 1 h, the product was extracted with 3 Â 20 mL of chloroform and

1258
A. Hadj-Bouazza et al.
extracts were evaporated. The crude product was purified using preparative TLC
(CH2Cl2/EtOH, 98/2, v/v) yielding 211 mg (50%). Rf = 0.56 (CH2Cl2/EtOH, 98/2, v/v);
[a]D = 50.1° (c = 0.33, CHCl3); IR: 2103 (N3), 1693 (C = O thym), 1651 (C = C),
1265 (C–O–C); 1H NMR (CDCl3) d: 9.12 (s, 1H, H-3), 7.27 (brs, 1H, H-6), 6.07 (t,
1H, J1’,2’ = 5.5, H-1’), 3.77 (m, 1H, H-4’), 3.63 (dd, 1H, J2’a,2’b = 13.2 Hz, H-2’a), 3.61
(dd, 1H, J3’a,3’b = 13.2 Hz, J3’a,4’ = 3.0 Hz, H-3’a), 3.51 (dd, 1H, H-2’b), 3.46 (dd, 1H,
J3’b,4’ = 5.4 Hz, H-3’b), 3.41 (dd, 1H, J5’a,5’b = 13.2 Hz, J5’a,4’ = 7.0 Hz, H-5’a), 3.35
(dd, 1H, J5’b,4’ = 4 Hz, H-5’b), 1.97 (brs, 3H, CH3); MS (DCI/NH3) m/z 358 (M Na+).
Compounds 12, 13 and 14 were prepared according to the procedure
described for 15 starting from 8 (635 mg, 1.69 mmol), 9 (146 mg, 0.40 mmol), and
10 (119 mg, 0.249 mmol), respectively.
1-[1-(1,3-Azidoisopropoxy)-2-azidoethyl]-3-tert-butoxycar-
bonylmethylthymine (12). Yield: 47.7% (364 mg); Rf = 0.74 (CH2Cl2/
EtOH, 98/2, v/v); [a]D = 94° (c = 1.23, CHCl3); IR: 2979 (C–H), 2104 (N3), 1707
1
(C = O thym), 1666 (C = O CO2tBu), 1651 (C = C), 1258 (C–O–C); H NMR
(CD3OD) d: 7.59 (d, 1H, JH6,CH3 = 1.0 Hz, H-6), 6.10 (t, 1H, J1’,2’ = 5.8 Hz, H-1’),
4.58 (s, 2H, CH2), 3.83 (m, 1H, H-4’), 3.75 (dd, 1H, J2’a,2’b = 13.1 Hz, H-2’a), 3.65
(dd, 1H, J3’a,3’b = 13.2 Hz, J3’a,4’ = 4.2 Hz, H-3’a), 3.58 (dd, 1H, H-2’b), 3.48 (dd, 1H,
J3’b,4’ = 5.5 Hz, H-3’b), 3.41 (m, 2H, H-5’a, H-5’b), 1.98 (d, 3H, JCH3,H6 = 1.0 Hz,
CH3), 1.47 (s, 9H, tBu); MS (DCI/NH3) m/z 472 (MNa+).
1-[1-(1-O-Benzoylmethyl-2-azidoethoxy)-2-azidoethyl]thymine
(13). Yield: 48% (80 mg); Rf = 0.70 (CH2Cl2/EtOH, 98/2, v/v); IR: 2940 (C–H),
2108 (N3), 1725 (C = O benzoyl), 1705 (C = O thym), 1650 (C = C), 1268 (C–O–
1
C); H NMR (CDCl3) d: 9.10 (s, 1H, H-3), 8.07–7.30 (m, 5H, Ar), 7.14 (q, 1H,
JH6,CH3 = 1.0 Hz, H-6), 6.08 (dd, 1H, J1’,2’a = 5.8 Hz, J1’,2’b = 5.1 Hz, H-1’), 4.38 (m,
1H, H-5’a), 4.37 (dd, 1H, J5’a,5’b = 12.5 Hz, J5’b,4’ = 4.8 Hz, H-5’b), 4.08 (m, 1H, H-
4’), 3.70 (dd, 1H, J3’a,3b’ = 12.8 Hz, J3’a,4’ = 5.0 Hz, H-3’a), 3.59 (dd, 1H, J3’b,4’ = 4.1
Hz, H-3’b), 3.58 (dd, 1H, J2’a,2’b = 12.8 Hz, H-2’a), 3.48 (dd, 1H, H-2’b), 1.61 (d, 3H,
JCH3,H6 = 1.0 Hz, CH3).
1-[1-(1-O-Benzoylmethyl-2-azidoethoxy)-2-azidoethyl]-3-tert-
butoxycarbonylmethyl thymine (14). Yield: 61.6% (81 mg); Rf = 0.50
(CH2Cl2/EtOH, 99/1, v/v); IR: 2925 (C–H), 2107 (N3), 1728 (C = O benzoyl), 1708
1
(C = O thym), 1670 (C = O CO2tBu), 1651 (C = C), 1271 (C–O–C); H NMR
(CD3OD) d: 7.93–7.26 (m, 5H, Ar), 7.15 (q, 1H, JH6,CH3 = 1.1 Hz, H-6), 6.11 (dd,
1H, J1’,2’a = 6.4 Hz, J1’,2’b = 4.7 Hz, H-1’), 4.54 (d, 1H, J = 16.5, CH2), 4.50 (d, IH,
J = 16.5, CH2), 4.42 (dd, 1H, J5’a,5’b = 12.2 Hz, J5’a,4’ = 6.6 Hz, H-5’a), 4.32 (dd, 1H,
J5’b,4’ = 3.28 Hz, H-5’b), 4.10 (m, 1H, H-4’), 3.70 (dd, 1H, J3a,3’b = 13.1, J3’a,4’ = 4.4
Hz, H-3’a); 3.58 (dd, 1H, J3’b,4’ = 5.8 Hz, H-3’b), 3.57 (dd, 1H, J2’a,2’b = 13.1 Hz, H-
2’a), 3.46 (dd, 1H, H-2’b), 1.61 (d, 3H, JCH3,H6 = 1.0 Hz, CH3), 1.46 (s, 9H, tBu); MS
(DCI/NH3) m/z 551 (MNa+).

New Acyclonucleosides
1259
1-[1-(1,3-Chloroisopropoxy)-2-chloroethyl]thymine (15). Com-
pound 7 (103 mg, 0.396 mmol) was stirred with pyridine (2 mL) under inert
atmosphere. Four equivalents of SOCl2 (0.33 mL) were added at 0°C. After 10 min
the mixture was stirred at room temperature for 3 days, then MeOH was added and
the solution was kept for 10 min at room temperature and concentrated. The crude
product was purified by preparatives TLC using CH2Cl2/EtOH (96/04, v/v),
compound 15 was obtained as yellow syrup (87 mg, 60.4%). Rf = 0.5 (CH2Cl2/
EtOH, 98/2, v/v); IR: 3185 (N–H), 3043 (C–H), 1688 (C = O thym), 1650 (C = C),
1
1260 (C–O–C); H NMR (CD3OD) d: 9.06(s, 1H, H-3), 7.21 (q, 1H, JH6,CH3 = 1.1
Hz, H-6), 6.09 (d, 1H, J1’,2’ = 6.4 Hz, H-1’), 3.98 (m, 1H, H-4’), 3.78 (dd, 1H,
J2’a,2’b = 11.9 Hz, H-2’a), 3.66 (dd, 1H, H-2’b), 3.65 (dd, 1H, J5’a,5’b = 11.9 Hz,
J5’a,4’ = 4.3 Hz, H-5’a), 3.64 (dd, 1H, J5’b,4’ = 5.5 Hz, H-5’b), 3.31 (m, 1H, H-3’a), 3.60
(dd, 1H, J3’a,3’b = 12 Hz, J3’b,4’ = 6.2 Hz, H-3’b), 1.97 (d, 3H, JCH3,H6 = 1, CH3). MS
(DCI/NH3) m/z 315 (MH+), 317 (MH+), 332 (MNH4+), 334 (MNH+4).
Compounds 16, 17 and 18 were prepared the same way as that described for
15 starting from 8 (103 mg, 0.275 mmol), 9 (206 mg, 0.566 mmol), and 10 (90 mg,
0.188 mmol), respectively.
1-[1-(1,3-Chloroisopropoxy)-2-chloroethyl]-3-tert-butoxycar-
bonylmethylthymine (16). Yield: 66% (78 mg), Rf = 0.68 (CH2Cl2/EtOH,
98/2, v/v); IR: 2930 (C–H), 1708 (C = O thym), 1670 (C = O CO2tBu), 1650
1
(C = C), 1255 (C–O–C); H NMR (CD3OD) d: 7.23 (brs, 1H, H-6), 6.10 (t, 1H,
J1’,2’ = 6.1 Hz, H-1’), 4.57 (s, 2H, CH2), 3.97 (m, 1H, H-4’), 3.77 (dd, 1H,
J2’a,2’b = 12.0 Hz, H-2’a), 3.76 (dd, 1H, J3’a,3’b = 12.2 Hz, J3’a,4’ = 5.5 Hz, H-3’a), 3.72
(dd, 1H, J3’b,4’ = 5.0 Hz, H-3’b), 3.67 (dd, 1H, H-2’b), 3.63 (dd, 1H, J5’a,5’b = 11.9 Hz,
J5’a,4’ = 1.3 Hz, H-5’a), 3.61 (dd, 1H, J5’b,4’ = 5.7 Hz, H-5’b), 1.98 (brs, 3H, CH3), 1.46
(s, 9H, tBu); MS (DCI/NH3) 451 (MNa+), 453 (MNa+).
1-[1-(1-O-Benzoylmethyl-2-chloroethoxy)-2-chloroethyl]thy-
mine (17). Yield: 60% (136 mg), Rf = 0.60 (CH2Cl2/EtOH, 98/2, v/v); IR: 2950
(C–H), 1730 (C = O benzoyl), 1699 (C = O thym), 1650 (C = C), 1275 (C–O–C);
1H NMR (CDCl3) d: 8.67 (s, 1H, H-3), 8.0–7.3 (m, 5H, Ar), 7.08 (q, 1H,
JH6,CH3 = 1.0 Hz, H-6), 6.2 (t, 1H, J1’,2’ = 6.1 Hz, H-1’), 4.46 (dd, 1H, J5’a,5’b = 12.1
Hz J5’a,4’ = 6.0 Hz, H-5’a), 4.43 (dd, 1H, J5’b,4’ = 4.0 Hz, H-5’b), 4.19 (m, 1H, H-4’),
3.80 (dd, 1H, J3’a,3’b = 12.2 Hz, J3’a,4’ = 5.5 Hz, H-3’a), 3.79 (dd, 1H, J2’a,2’b = 12.0
Hz, H-2’a), 3.75 (dd, 1H, J3’b,4’ = 5.2 Hz, H-3’b), 3.63 (dd, 1H, H-2’b), 1.61 (d, 3H,
JCH3,H6 = 1.0 Hz, CH3).
1-[1-(1-O-Benzoylniethyl-2-chloroethoxy)-2-chloroethyl]-3-
tert-butoxycarbonylmethyl thymine (18). Yield 45.4% (44 mg), Rf =
0.52 (CH2Cl2/EtOH, 98/2, v/v); IR: 2955 (C–H), 1725 (C = O benzoyl), 1699
1
(C = O thym), 1666 (C = O CO2tBu), 1651 (C = C), 1270 (C–O–C); H NMR
(CD3OD) d: 8.0–7.4 (m, 5H, Ar), 7.10 (q, 1H, JH6,CH3 = 1.0 Hz, H-6), 6.15 (t, 1H,

1260
A. Hadj-Bouazza et al.
J1’,2’ = 6.0 Hz, H-1’), 4.52 (s, 2H, CH2), 4.48 (dd, 1H, J5’a,5’b = 12.1 Hz, J5’a,4’ = 7.0
Hz, H-5’a), 4.39 (dd, 1H, J5’b,4’ = 3.2 Hz, H-5’b), 4.18 (m, 1H, H-4’), 3.79 (dd, 1H,
J3’a,3’b = 12.0 Hz, J3’a,4’ = 5.5 Hz, H-3’a), 3.77 (m, 1H, H-3’b), 3.73 (dd, 1H,
J2’a,2’b = 11.9 Hz, H-2’a), 3.64 (dd, 1H, H-2’b), 1.60 (d, 3H, JCH3,H6 = 1.0 Hz, CH3),
1.45 (s, 9H, tBu).
1-[1-(1-O-Hydroxymethyl-2-azidoethoxy)-2-azidoethyl]thy-
mine (19). Compound 13 (60 mg, 0.145 mmol) was dissolved in 3 mL of
methanol and a solution of ammonia in methanol 7M (2 mL, 100 eq). After 4 days,
the solution was evaporated and the crude product was purified using preparatives
TLC (CH2Cl2/EtOH, 92/8, v/v). The expected compound was isolated in 69% yield
(31 mg). Rf = 0.40 (CH2Cl2/EtOH, 95/5, v/v); IR: 3300 (O–H), 2923 (C–H), 2105
1
(N3), 1690 (C = O thym), 1650 (C = C), 1263 (C–O–C); H NMR (CD3OD) d:
7.57 (q, 1H, JH6,CH3 = 1.1 Hz, H-6), 6.04 (t, 1H, J1’,2’ = 6.0 Hz, H-1’), 3.72 (dd, 1H,
J2’a,2’b = 13.1 Hz, H-2’a), 3.67 (m, 1H, H-4’), 3.66 (dd, 1H, J5’a,4’ = 12.8 Hz,
J5’a,4’ = 3.8 Hz, H-5’a), 3.62 (dd, 1H, J3’a,3’b = 13.0 Hz, J3’a,4’ = 3.8 Hz, H-3’a), 3.55
(dd, 1H, J3’b,4’ = 5.8 Hz, H-3’b), 3.51 (dd, 1H, J5’b,4’ = 5.5 Hz, H-5’b), 3.43 (dd, 1H,
H-2’b), 1.90 (d, 3H, JCH3,H6 = 1.1 Hz, CH3); MS (DCI/NH3) m/z 311 (MH+), 328
(MNH+4).
Compound 20 was prepared according to the procedure described for 19
starting from 14 (116 mg, 0.22 mmol).
1-[1-(1-Hydroxymethyl-2-azidoethoxy)-2-azidoethyl]-3-tert-
butoxycarbonylmethyl thymine (20). Yield: 79.3% (74 mg), Rf = 0.61
(CH2Cl2/EtOH, 98/2, v/v), IR: 3300 (O–H), 2923 (C–H), 2105 (N3), 1690 (C = O
1
thym), 1666 (C = O CO2tBu), 1650 (C = C), 1255 (C–O–C); H NMR (CD3OD)
d: 7.64 (q, 1H, JH6,CH3 = 1.0 Hz, H-6), 6.07 (t, 1H, J1’,2’ = 5.9 Hz, H-1’), 4.55 (s, 2H,
CH2), 3.73 (dd, 1H, J2’a,2’b = 13.0 Hz, J2’a,1’ = 5.9 Hz, H-2’a), 3.69 (m, 1H, H-5’a),
3.69 (m, 1H, H-4’), 3.63 (dd, 1H, J3’a,3’b = 13.2 Hz, J3’a,4’ = 3.9 Hz, H-3’a), 3.55 (dd,
1H, J5’a,5’b = 12.4 Hz, J5’b,4’ = 3.4 Hz, H-5’b), 3.51 (dd, 1H, J3’b,4’ = 5.3 Hz, H-3’b),
3.46 (dd, 1H, H-2’b), 1.94 (d, 3H, JCH3,H6 = 1.0 Hz, CH3), 1.46 (s, 9H, tBu).
5-(Chloromethyl)-3-(thymin-1-yl)-1,4-dioxane (21). Compound
17 (30 mg, 0.075 mmol) was dissolved in 2 mL of methanol and a solution of
ammonia in methanol 7 M (1 mL, 7 mmol). After 4 days, the solution was
evaporated and the crude product was purified using preparatives TLC (CH2Cl2/
EtOH, 98/2, V/V). The dioxane nucleoside 21 was isolated in 82% (16 mg). Rf = 0.50
(CH2Cl2/EtOH, 98/2, v/v), IR: 3200 (N–H), 3000 (C–H), 1690 (C = O thym), 1650
1
(C = C), 1260 (C–O–C); H NMR (CD3OD), isomer 1 = d: 7.86 (q, 1H, JH6’,CH3
=
1.1 Hz, H-6’), 6.12 (dd, 1H, J3,2b = 2.3 Hz, J3,2a = 6.1 Hz, H-3), 4.85 (dd, 1H,
J2a,2b = 10.5, H-2a), 4.68 (dd, 1H, H-2b), 4.12 (m, 1H, H-5), 3.71 (dd, 1H, J6a,5 = 3.8
Hz, J6a,6b = 11.7 Hz, H-6a), 3.70 (dd, J6b,5 = 3.4 Hz, H-6b), 3.62 (dd, 1H, J7a,5 = 3.1
Hz, J7a,7b = 11.8 Hz, H-7a), 3.61 (dd, J7b,5 = 3.1 Hz, H-7b), 1.95 (d, 1H, CH3). isomer

New Acyclonucleosides
1261
2 = d: 7.79 (q, 1H, JH6’,CH3 = 1.1 Hz, H-6’), 6.10 (dd, 1H, J3,2b = 2.3 Hz, J3,2a = 6.0
Hz, H-3), 4.80 (dd, 1H, J2a,2b = 10.4, H-2a), 4.70 (dd, 1H, H-2b), 4.10 (m, 1H, H-5),
3.74 (dd, 1H, J6a,5 = 3.4 Hz, J6a,6b = 11.6 Hz, H-6a), 3.68 (dd, J6b,5 = 3.3 Hz, H-6b),
3.60 (dd, 1H, J7a,5 = 3.6 Hz, J7a,7b = 11.8 Hz, H-7a), 3.58 (dd, J7b,5 = 2.1 Hz, H-7b),
1.95 (d, 1H, CH3); MS (DCI/NH3) m/z 261 (MH+), 278 (MNH4+).
1-[1-(1,3-Dihydroxyisopropoxy)-2-hydroxyethyl]-3-carboxyme-
thylthymine (22). This compound was prepared by the reaction of 8 (31 mg,
0.08 mmol) with TFA (1 mL) at room temperature for 2 h. After purification by
preparative TLC using butanol/water/acetic acid (50/25/25, v/v/v), the product 21
was isolated in 98.3% yield (25 mg). Rf = 0.25 (CH2Cl2/EtOH, 90/10, v/v); IR: 3384
(O–H), 2935 (C–H), 1696 (C = O thymine), 1698 (C = O CO2H), 1635 (C = C).
1255 (C–O–C); 1H NMR (CD3OD) d: 7.65 (q, 1H, JH6,CH3 = 1.1 Hz, H-6), 5.97 (t,
1H, J1’,2’ = 5.4 Hz, H-1’), 4.67 (d, 1H, J = 16.9 Hz, CH2), 4.62 (d, 1H, J = 16.9 Hz,
CH2), 3.77 (dd, 1H, J2’a,2’b = 11.9 Hz, H-2’a), 3.70 (dd, 1H, H-2’b), 3.68 (m, 1H, H-
5’a), 3.68 (m, 1H, H-5’b), 3.64 (m, 1H, H-4’), 3.55 (m, 1H, H-3’a), 3.55 (dd, 1H,
J3’a,3’b = 11.4 Hz, J3’b,4’ = 4.6 Hz, H-3’b), 1.93 (d, 3H, JCH3,H6 = 1.1 Hz, CH3).
Compounds 24, 25 and 26 were prepared in a manner similar to that
described for 23 starting from 12 (68 mg, 0.151 mmol), 16 (25 mg, 0.058 mmol),
and 20 (40 mg, 0.094 mmol), respectively.
1-[1-(1,3-Azidoisopropoxy)-2-azidoethyl]-3-carboxymethylthy-
mine (23). Yield: 87.6% (52 mg), Rf = 0.18 (CH2Cl2/EtOH, 98/2, v/v); IR: 3300
(O–H), 2930 (C–H), 2104 (N3), 1702 (C = O thym), 1667 (C = O CO2H), 1644
1
(C = C), 1288 (C–O–C); H NMR (CD3OD) d: 7.34 (s, 1H, H-6), 6.07 (t, 1H,
J1’,2’ = 5.8 Hz, H-1’), 4.60 (s, 2H, CH2), 3.80 (m, 1H, H-4’), 3.70 (dd, 1H, J2’a,2’b
=
13.0 Hz, H-2’a), 3.60 (dd, 1H, J3’a,3’b = 13.1 Hz, J3’a,4’ = 4.0 Hz, H-3’a), 3.50 (dd, 1H,
H-2’b), 3.45 (dd, 1H, J3’b,4’ = 5.5 Hz, H-3’b), 3.38 (m, 2H, H-5’a, H-5’b), 1.97 (s, 3H,
CH3); MS (DCI/NH3) m/z 416 (MNa+), 432 (MK+).
1-[1-(1,3-Chloroisopropoxy)-2-chloroethyl]-3-carboxyme-
thylthymine (24). Yield: 83.1% (18 mg), Rf = 0.25 (CH2Cl2/EtOH, 98/2, v/v);
IR: 3310 (O–H), 2927 (C–H), 1704 (C = O thym), 1667 (C = O CO2H), 1649
1
(C = C), 1255 (C–O–C); H NMR (CD3OD) d: 7.63 (q, 1H, JH6,CH3 = 1.2 Hz, H-
6), 6.14 (dd, 1H, J1’,2’a = 6.0 Hz, J1’,2’b = 6.7 Hz, H-1’), 4.68 (d, 1H, J = 16.9 Hz,
CH2), 4.61 (d, 1H, J = 16.9 Hz, CH2), 4.07 (1H, m, H-4’), 3.93 (dd, 1H, J2’a,2’b = 11.9
Hz, H-2’a), 3.88 (dd, 1H, H-2’b), 3.83 (dd, 1H, J5’a,5’b = 11.9 Hz, J5’a,4’ = 5.1 Hz, H-
5’a), 3.79 (dd, 1H, J5’b,4’ = 4.9 Hz, H-5’b), 3.68 (dd, 1H, J3’a,3’b = 12.1 Hz, J3’a,4’ = 4.4
Hz, H-3’a), 3.63 (dd, 1H, J3’b,4’ = 6.0 Hz, H-3’b), 1.95 (d, 3H, JCH3,H6 = 1.2 Hz,
CH3); MS (DCI/NH3) m/z 373 (MH+), 375 (MH+), 390 (MNH4+), 392 (MNH+4).
1-[1-(-1-Hydroxymethyl-2-azidoethoxy)-2-azidoethyl]-3-car-
boxymethylthymine (25). Yield: 52% (18 mg); Rf = 0.40 (CH2Cl2/EtOH,

1262
A. Hadj-Bouazza et al.
98/2, v/v); IR: 3250 (O–H), 2923 (C–H), 2105 (N3), 1703 (C = O thym), 1670
1
(C = O CO2H), 1650 (C = C), 1265 (C–O–C); H NMR (CD3OD) d: 7.56 (brs,
1H, H-6), 6.07 (t, 1H, J1’,2’ = 4.2 Hz, H-1’), 3.70 (m, 1H, H-5’a), 3.69 (m, 1H, H-4’),
3.68 (dd, 1H, J2’a,2’b = 12.5 Hz, H-2’a), 3.56 (dd, 1H, J3’a,3’b = 13.5 Hz, J3’a,4’ = 3.0
Hz, H-3’a), 3.54 (m, 1H, H-5’b), 3.50 (m, 1H, H-2’b), 3.46 (dd, 1H, J3’b,4’ = 4.8 Hz, H-
3’b), 3.38 (s, 2H, CH2), 1.97 (brs, 3H, CH3); MS (DCI/NH3) m/z 369 (MH+),
386 (MNH+4).
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